title: Zinc signals are essential for lipopolysaccharide-induced signal transduction in monocytes.
abstract: Cytosolic alterations of calcium ion concentrations are an integral part of signal transduction. Similar functions have been hypothesized for other metal ions, in particular zinc (Zn(2+)), but this still awaits experimental verification. Zn(2+) is important for multiple cellular functions, especially in the immune system. Among other effects, it influences formation and secretion of pro-inflammatory cytokines, including TNF-alpha. Here we demonstrate that these effects are due to a physiological signaling system involving intracellular Zn(2+) signals. An increase of the intracellular zinc ion concentration occurs upon stimulation of human leukocytes with Escherichia coli, LPS, Pam(3)CSK(4), TNF-alpha, or insulin, predominantly in monocytes. Chelating this zinc signal with the membrane permeable zinc-specific chelator TPEN (N,N,N',N'-tetrakis-(2-pyridyl-methyl)ethylenediamine) completely blocks activation of LPS-induced signaling pathways involving p38 MAPK, ERK1/2, and NF-kappaB, and abrogates the release of proinflammatory cytokines, including TNF-alpha. This function of Zn(2+) is not limited to monocytes or even the immune system, but seems to be another generalized signaling system based on intracellular fluctuations of metal ion concentrations, acting parallel to Ca(2+).
authors.affiliation: Institute of Immunology, Department of Cell Biology, Rheinisch-Westfälische Technische Hochschule Aachen University Hospital, Aachen, Germany.
authors.forename: Hajo
authors.initials: H
authors.lastname: Haase
authors.forename: Julia L
authors.initials: JL
authors.lastname: Ober-Blöbaum
authors.forename: Gabriela
authors.initials: G
authors.lastname: Engelhardt
authors.forename: Silke
authors.initials: S
authors.lastname: Hebel
authors.forename: Antje
authors.initials: A
authors.lastname: Heit
authors.forename: Holger
authors.initials: H
authors.lastname: Heine
authors.forename: Lothar
authors.initials: L
authors.lastname: Rink
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D002413:Cations, Divalent / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D007424:Intracellular Fluid / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000276:immunology; D015032:Zinc / Q000378:metabolism / Q000502:physiology*
chemical_list: D002413:Cations, Divalent; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D015032:Zinc; D002118:Calcium